Fig. 3

DAPK1 dysregulation induces tau hyperphosphorylation and microtubule injury in AD. Neuronal tau is essential for regulating microtubule dynamics. DAPK1 dysregulation contributes to tau pathology through two mechanisms. First, DAPK1 interacts with Pin1 and suppresses its activity by directly phosphorylating the Ser71 residue of Pin1. Upon phosphorylation, the Pin1-mediated cis-to-trans isomerization of pThr231-Pro motif in tau protein is decelerated, leading to the accumulation of cis pT231-tau that is resistant to degradation/dephosphorylation and has lower microtubule binding affinity but higher aggregation propensity. Second, it has been reported that DAPK1 directly interacts with tau and phosphorylates its Ser262 residue, thereby exacerbating neuronal tau pathologies